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Patent 1333770 Summary

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(12) Patent: (11) CA 1333770
(21) Application Number: 579561
(54) English Title: IMPLANTABLE, BIODEGRADABLE SYSTEM FOR RELEASING ACTIVE SUBSTANCE
(54) French Title: SYSTEME BIODEGRADABLE ET IMPLANTABLE POUR LA LIBERATION DE SUBSTANCES ACTIVES
Status: Expired
Bibliographic Data
(52) Canadian Patent Classification (CPC):
  • 167/166
(51) International Patent Classification (IPC):
  • A61K 47/34 (2006.01)
  • A61K 9/00 (2006.01)
  • A61K 9/20 (2006.01)
  • A61K 9/22 (2006.01)
  • A61K 9/52 (2006.01)
(72) Inventors :
  • STRICKER, HERBERT (Germany)
  • ENTENMANN, GUNTHER (Germany)
  • KERN, OTTO (Germany)
  • MIKHAIL, MICHEL (Germany)
  • ZIERENBERG, BERND (Germany)
(73) Owners :
  • BOEHRINGER INGELHEIM INTERNATIONAL GMBH (Germany)
(71) Applicants :
(74) Agent: FETHERSTONHAUGH & CO.
(74) Associate agent:
(45) Issued: 1995-01-03
(22) Filed Date: 1988-10-07
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
P 37 34 223.1 Germany 1987-10-09

Abstracts

English Abstract






The invention relates to biodegradable implants
for releasing an active substance. The implants
comprise a poly-D,L-lactide based carrier material
containing the active substance and at least one
additive material selected from solvents, plasticizers,
pore-forming agents and low molecular weight polymers
and may be produced with variable disintegration
and active substance release rates.


Claims

Note: Claims are shown in the official language in which they were submitted.


- 25 -

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A biodegradable implant comprising a poly-D,L-lactide
based, physiologically active substance containing carrier mater-
ial, said carrier material further containing at least one
additive material selected from pore-forming agents, low molecular
weight polymers, and up to about 10% by weight relative to the
carrier material weight of physiologically acceptable solvents or
plasticizers.


2. An implant as claimed in claim 1 wherein said carrier
material contains at least one said additive material selected
from: water-soluble pore-forming agents in an amount of up to 50%
by weight; low molecular weight polymers of lactic or glycolic
acid in an amount of up to 60% by weight; and physiologically
acceptable solvents or plasticizers in an amount of up to 10% by
weight; the percentages by weight being relative to the weight of
the carrier material.


3. An implant as claimed in claim 1 wherein said carrier
material consists of poly-D,L-lactide.


4. An implant as claimed in claim 1, 2 or 3 wherein said
carrier material comprises a copolymer of D,L-lactide and glycolide,
having a glycolide content not exceeding 50% by weight.



5. An implant as claimed in claim 1, 2 or 3 wherein said
carrier material contains up to 10% by weight relative to the
carrier material weight of an acetic acid ester.


- 26 -

6. An implant as claimed in claim 1, 2 or 3, wherein said
carrier material contains up to 60% by weight of low molecular
weight polylactic acid or up to 50% by weight of lactose, the
percentages by weight being relative to the carrier material
weight.


7. An implant as claimed in claim 1, 2 or 3 in the form
of a tubular or rod-like member.


8. An implant as claimed in claim 7 wherein said member
has a layered structure.


9. An implant as claimed in claim 7 which comprises at
least one rolled film.


10. An implant as claimed in claim 9 comprising at least
one rolled multi-layered film.


11. An implant as claimed in claim 7 which comprises a
multi-layer rolled film having layers of different compositions.


12. An implant as claimed in claim 1, 2 or 3 in the form
of a hollow active substance containing tubular member provided
with an outer casing which is impermeable to said active substance.



13. An implant as claimed in claim 1, 2 or 3, containing
as active substance a hormone or cytostatic agent.


14. An implant as claimed in claim 1, 2 or 3 containing
clenbuterol hydrochloride as physiologically active substance.


15. A process for the preparation of an implant as claimed

- 27 -


in claim 1 which process comprises : forming a solution of said
carrier material containing said at least one additive material,
said physiologically active substance pouring said solution to
form a film; at least partially removing the solvent from said
film to form a dried film; and forming one or more said dried
films into a tubular or rod-like member of desired dimensions.


16. A process as claimed in claim 15 wherein removal of
said solvent to yield said dried film is so effected as to leave a
residual solvent content of about 10% by weight relative to the
carrier material weight.


17. A process as claimed in claim 16 wherein after said
removal of solvent at least one further carrier material layer is
deposited on said film and solvent removal is effected to form a
multi-layer dried film.


18. A process as claimed in claim 15, 16 or 17 wherein
solvent removal is so effected on said film or on said tubular or
rod-like member formed therefrom as to leave a residual solvent
content of from 1 to 7% by weight relative to the carrier material
weight.


19. A process as claimed in claim 15, 16 or 17 wherein at
least two films of different compositions are rolled up to form a
tubular or rod-like member.


20. A process for the preparation of an implant as claimed
in claim 1 which process comprises extruding a mixture of said
carrier material, physiologically active substance and additive



material and forming the extrudate into tubular or rod-like
members of desired dimensions.



21. A process as claimed in claim 15, 16 or 17 wherein said
tubular or rod-like member is provided with an outer casing.


22. A composition which comprises a poly-lactide carrier
material, a physiologically active substance and an additive
material selected from pore-forming agents, low molecular weight
polymer and physiologically acceptable solvents and plasticizers
in an amount up to 10% by weight based on the weight of carrier
material.


23. Use of a biodegradable implant containing a physiologi-
cally active substance as claimed in any one of claims 1 to 3 and
8 to 11 for treatment of the human or non-human animal body.

28

Description

Note: Descriptions are shown in the official language in which they were submitted.


- ~ 333770
~N 53 336

Biodegradable implant

The present invention relates to a biodegradable
implant, i.e. an implantable system for releasing
an active substance.

Numerous implantable or injectable systems for
releasing active substance are known from the prior
art. .Systems of this kind are preferably used
when an active substance has to be administered
over a fairly long period of time and oral administration
is impossible or unreliable or impractical. In
addition to use in humans, parenteral preparations
for use in animal husbandry or for the treatment
of animal diseases are of special interest. The
conventional method of administering drugs by adding
them to the feed has the serious disadvantage that
the auantity of drug taken is not sufficiently
accurate.

Implantable systems for releasing active substance
should satisfy the following criteria:

The active substance should be released at a constant
rate over a long period of time and the implant
should be broken down within a reasonable interval
after the active substance has been released so
that there is no need to operate to remove the
implant. It is also advantaqeous if the rate of
release of active substance from the carrier can
be made variable so that it can be matched both
to the active substance and also to the particular
treatment.

1 333770
-- 2
An ob~ective of this invention is to provide a
biodegradable implant which can release an active
substance over a fairly long period of time at
a substantially constant rate and which can be
broken down within a reasonable time.

T~e have found that this oh~ective may be achieved
by means of an implant comprising a poly-D,L-lactide-
based, additive-containing carrier material.

~hus, in one aspect the present invention provides
a biodegradable implant comprising a poly-D,L-lactide
based, physiologically active substance containing
carrier material ana, optionally, at least one
pharmaceutical excipient, said carrier material
further containing at least one additive material
selected from pore-forming agents, low molecular
weight polymers, and up to about 10% by weight
relative to the carrier material weight of physiologically
acceptable solvents or plasticizers.

In the active substance releasing implants of the
invention, the additive materials in the carrier
material are conveniently selected from: physiologically
acceptable solvents or plasticizers, preferably
acetic acid esters, in an amount of up to 10% by
weight; suspended water-soluble pore-forming agents,
such as for example lactose, in an amount of up
to 50% by weight; low molecular weight polymers,
preferably biodegradable polymers, especially preferably
polymers and copolymers of lactic acid and glycolic
acid, in an amount of up to 60~ by weiqht; the
weight percentages being relative to the carrier
material weight.

Poly-D,L-lactides having a wide range of molecular
weights are known. For the carrier material of

1 333770

the implant according to the invention, poly-D,L-
lactides with mid-range number average molecular
weights are preferred, for example polymers having
an inherent viscosity of between 0.15 and 4.5 (measured
in chloroform at 25C, at a test concentration
C of 100 mg/ml).

In a preferred embodiment of the invention, the
carrier material consists of poly-D,L-lactide.

In another embodiment of the invention, the carrier
material comprises a copolymer of D,L-lactide and
glycolide; in this embodiment the portion of glycolide
in the copolymer should not exceed 50% by weight.

Surprisingly, it has been found that the rate of
decomposition of the implant of the invention can
be controlled by incorporating in the carrier material
a defined content of a physiologically acceptable
solvent or plasticiser, such as an acetic acid
ester, or a mixture of solvents which will quantitatively
remain in the polymer even after lengthy storage.
This is of crucial importance, since on the one
hand the implant must be broken down rapidly enough
but on the other hand excessively rapid decomposition
of the implant will lead to uncontrolled release
of the active substance. The solvent or plasticiser,
preferably an acetic acid ester, is incorporated
in the carrier material in amounts of up to 10%
by weight relative to the weiqht of the carrier
material whereby increasing amounts of the solvent
or plasticiser will accelerate the breakdown of
the carrier material. A composition which gives
a release of active substance corresponding to
a half-life of between 3 and 60 days, followed
by breakdown of the implant within about 120 days
thereafter is favourable. In individual cases,

~ :333770
-- 4
however, shorter rates of release and breakdown
may be advantageous.

~Surprisingly, it has alsobeen found that, although
the incorporation of the poly-D,L-lactide solvent
or plasticiser (e.g. an acetic acid ester) influences
the rate of decomposition of the implant it has
no significant effect on the release of the active
substance.

Acetic acid esters which can be used for the purposes
of the invention include the alkyl esters of acetic
acid, such as the C1 5alkyl esters, e.g. the methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert.-butyl, n-pentyl, sec.-pentyl, isopentyl and
tert.-pentyl esters. Ethyl acetate is particularly
preferred.

The rate of decomposition of the implant may also
be controlled by the addition of low molecular
weight polymers. Thus in another embodiment, the
implant according to the invention may contain
up to 60% (by weight relative to the weight of
the carrier material) of low molecular weight polymers
such as, for example, poly(L-lactic acid~, poly(D-
lactic acid~, poly(D,L-lactic acid), poly(qlycolic
acid), poly(L-lactic acid-co-glycolic acid), poly(D-
lactic acid-co-qlycolic acid) and poly(D,L-lactic
acid-co-glycolic acid). Poly(L-lactic acid~ and
poly(D,L-lactic acid) are preferred. For these
low molecular weight polymers the number average
molecular wei~hts (determined by titration of the
terminal groups~ conveniently range from 500 to
5000, preferably from 1500 to 2500.

The incorporation of these polymers into the carrier
material, either on their own or in coniunction

1 333770
-- 5
with a solvent or plasticizer such as an acetic
acid ester, makes it possible to control the rate
of decomposition of the implant.

Besides influencing the decomposition rate of the
implant by incorporating polymers, solvents or
plasticizers into the carrier material, it is also
possible to influence the active substance release
rate, for example:

a) by incorporating into the carrier material
a pore-forming agent, such as for example
lactose,
b) by selecting the physical state of the active
substance (e.g. in solution, in suspension
or in particulate form having particular
particle sizes~,
c) by selecting the physical form of the carrier
material (e.g. monolithic, polydispersed,
or laminated forms~.

Therefore, in addition to compounds which influence
the rate of decomposition of the carrier material,
the implant according to the invention may also
contain additive substances in the form of pore-
forming agents which make it possible to control
the release of active suhstance.

Pore-forming agents which may be used according
to the invention include, for example, water soluble
pharmaceutically accepta~le monosaccharides and
disaccharides. Lactose is preferred, but glucose,
fructose, xylose, galactose, sucrose, maltose,
saccharose and related compounds such a mannitol,
xylitol and sorbitol may also be used. Other suitable
excipients which may be used include salts such
as the lactates, glyconates or succinates of sodium,
potassium or magnesium.

1 333 7 70
-- 6 --
Rapid and immediate release of the active substance
from the carrier material immediately after implantation
is achieved when the rate of release of the pore-
forming agent is very much greater than that of
the active substance. This is the case, for example,
when the pore-forming agent, e.g. lactose, has
good solubility and a small particle size. A retarded
accelerated release of the active substance is
achieved when the solubility of the pore-forming
agent is very much less than that of the active
substance; this occurs, for example, when the pore-
forming agent has poor water solubility. The delayed
accelerated release of the active substance ensures
that the linear release curve of the active substance
is reliably ensured even over long periods of administration.

Using the parameters described, it is possible
to produce implants which have individually selected
release and breakdown rates.

The implant according to the invention in monolithic
form (i.e. in the form of a continuous mass~ may
be implanted or injected. Conveniently the monolithic
implants are in the form of rods or tubular members.
The rods are conveniently of such dimensions that
they can be implanted by means of an injection
needle or a trocar. A rod may be, for example,
about 3 cm long and about 2.8 mm in diameter.

Certain exemplary embodiments of the invention
will be described hexeinafter with reference to
the accompanying drawings, in which:-

Figure 1 is a schematic partial cross-section through
an implant according to the invention in encased
hollow tubular member form (type E~;

1 333770
-- 7
Figure 2 to 7 and 11 are graphs showing the degradation
with time of implants according to the invention;

and Figures 8 to 10 and 12 are graphs showing the
active substance release with time of implants
according to the invention.

The following embodiments of the implant of the
invention, described hereinafter, are preferred:

A) solid rods
B) rolled up films
C) encased rods
D) tubular members
E) encased tubular members

All the embodiments of the implant according to
the invention may be of laminated construction
and may be produced, for example, by the following
methods, which themselves represent further aspects
of the invention.

Thus in another aspect, the present invention provides
a process for the preparation of implants according
to the invention, which process comprises: forming
a solution of said carrier material containing
said at least one additive material, said physiologically
active substance and, optionally, at least one
said pharmaceutical excipient; pouring said solution
to form a film; at least partially removing the
solvent from said film to form a dried film; and
forming one or more said dried filmsinto a tubular
or rod-like member of desired dimensions.

The active substance may be distributed within,
e.g. dissolved or suspended with, the dissolved
polymeric carrier material, e.g. with ethyl acetate

1 333770

as solvent, and the additive material or any further
additive material may be combined therewith. If
desired, other pharmaceutical adiuvants may be
added to the dissolved polymeric carrier material
in addition to the active substance and the additive
material. The carrier material solution is then
poured out onto a surface and dried, i.e. the solvent
is at least partially removed, to form a film.
The drying conditions may particularly preferably
be chosen so that a desired residual amount of
solvent remains in the polymeric carrier material,
generally an amount of between 1 and 7% by weight.
The dried films preferably have a layer thickness
of between 30 and 1000 micrometers, especially
preferably about 100 micrometers. Apparatus and
methods for producing these films are known to
those skilled in the art and require no further
comment. It goes without saying that the drying
process must be carried out with a certain degree
of care (e.g. slowly and with minor variations
in temperature and vacuum humidity) to ensure that
the films stay flat.

Multi-layer films may be obtained by re-applying
polymer solution (with or without active substance~.

After the film is dry it may be cut up into rods
of the desired length to form implants of tyPe
A.

Implants of type B may be produced by rolling up
into rod like shapes one or more single- or multi-
layer films. The film or at least one of the films
used will contain the active substance. However,
the thickness of the films used to produce the
implants of type B may be substantially less than
those used to produce the implants of type A, films

1 333770

of between 30 and 500 micrometers, preferably between
70 and 90 micrometers, generally being used. After
drying, the films are cut and rolled up into rods
of the required diameter, e.g. up to about 3 mm,
which may then be cut to the desired length. The
rods may be rolled up so as to leave a central
cavity. In constructing a laminated implant of
type B, it is also possible to lay several films
one over the other or, preferably, to pour them
one over the other and then to roll them up to
form a rod. By combining several layers of film,
active substances can easily be combined and layers
with different concentrations of active substance
can be used. The individual layers may thus have
different release rates.

As well as an alternating layer sequence it is
also possible to produce a rolled core and then
to apply additional layers of film on the outside.

By using layers of film with different release
characteristics, it is possible to produce an implant
which will release different active substances
in a predetermined time sequence. It is not absolutely
necessary for all the film layers to contain active
substances.

When producing the implant of type B according
to the invention, the films should preferably have
a relatively high content of residual solvent ~e.g.
about 10~ when they are rolled up. This prevents
the films from becoming brittle. nnce rolled up,
the rod may then be subiected once more to a drying
process in order to achieve the desired residual
solvent content.

~ 33311

-- 10 --
Alternatively, implants of types C, D and E may
advantageously be produced by extrusion or injection
moulding of granules of active substance and carrier
material polymer or copolymer, optionally together
with additives such as polylactic acid, a plasticiser
such as triacetin or a pore-forming agent such
as lactose.

Thus in a still further aspect the invention provides
a process for the preparation of implants according
to the invention, which process comprises extruding
a mixture of said carrier material, physiologically
active substance, additive material and, optionally,
pharmaceutical excipient and forming the extrudate
into tubular or rod-like members of desired dimensions.

The tubular or rod-like implant may, if desired,
also be provided with an outer casing which may
be permeable or impermeable to the active substance.
The release of active substance from the encased
forms C and E may take place by various methods
depending on the construction of the implant used.
Implants of type C contain a solid core containing
the active substance and are surrounded by a
"porous" casing. The active substance suspended
in the core diffuses through pores in the casing
created by the dissolving out of a pore forming
agent, lactose for example. The critical release
factors therefore include the degree of charging
of the casing and the particle si~e of the pore-
forming agent, e.g. lactose.

By contrast with the encased forms of type ~, the
implant of type E consists of a hollow tubular
member containing the active substance, the outer
surface of which is encased in a sheath which is
impermeable to the active substance.

1 33377~
-- 11 --
~ith implants of type E, provided that the casing
is free from pores and impervious, the active substance
in the tubular member can only be released into
the central cavity of the tubular body. In this
sytem, the channels, i.e. diffusion paths for the
active substance, lengthen with time, and this
is compensated for by the increasing quantity of
active substance in a segment as the distance from
the cylinder axis increases.

Referring to the accomanying drawings, figure 1
is a schematic cross section through an embodiment
of an implant according the invention of type E.
The tubular core has a hollow central cavity 3,
contains particles 2 of active substance and is
provided with an outer impervious casing 1.

Crucial release factors for implants of type E,
in addition to the breakdown of the polymeric carrier
material and the degree of charging, include the
dimensions of the tubular implant such as its length
and internal diameter. It goes without saying
that, in the case of implants of type E, the casing
which is impervious to the active substance is
also biodegradable. Conveniently it comprises
a biodegradable polymer, preferably a poly-D,L-
lactide. A ma~or advantage of the implants thus
formed is that the active substance is released
in a substantially linear manner.

Implants of this type may also ~e produced using
films produced as described hereinbefore, the outer
film consisting of a layer which is free from and
impervious to the active substance.

Experiments have shown that the implants produced
by the "solvent method" (types A and B for example~

1 3~377~
- 12 -
have different breakdown characteristics from implants
produced by extrusion, i.e. the extruded members
are broken down more slowly despite having the
same polymer composition (see Fig. 2 hereto).
The difference may be due to the fact that in extrusion
it is not readily possible to achieve a defined,
higher residual solvent content because of the
relatively high temperatures during extrusion.

Implants according to the invention produced by
extrusion or injection moulding may conveniently
be produced using a carrier material comprising
a poly-D,L-lactide having a inherent viscosity
of between 0.15 and 1Ø Polymers of low inherent
viscosity (~ = 0.15) may be processed even at temperatures
below 100C, which is advantageous for the thermal
stress on the drugs added thereto.

Implants produced from a low inherent viscosity
poly-D,L-lactide not only release the active substance
more rapidly but also show faster decomposition
of the implant than is the case with polymers with
higher inherent viscosities (greater than 0.3),
which means that, if desired, an implant may be
produced which breaks down after only about 10
weeks.

Low viscosity poly-D,L-lactides may be prepared
from higher viscosity poly-D,L-lactides by partial
hydrolysis.

The release of active substance from the implants
according to the invention may be delayed by providing
an additional coating of low molecular weight poly-
D,L-lactide which contains no active substance
but which is permeable to the active substance.
This prevents the active substance from being released

1 333770
- 13 -
too quickly in the initial phase directly after
implanting.

Suitable active substances for incorporation in
the implants of the invention include those which
may be distributed in suspensed form in the polymeric
carrier material, especially the water-soluble
salt forms of bases, such as hydrochlorides or
hydrobromides. ~lenbuterol hydrochloride is particularly
preferred.

Furthermore, in the field of veterinary medicine,
the groups of substances and compounds listed below
may be used in the implants according to the invention.

glucocorticoids for inducing labour, e.g.
dexamethasone, betamethasone, flumethasone,
the esters and derivatives thereof, gestagens
for synchronising heat, or for suppressing
heat and rut;

~2-adrenergics for the treatment and prevention
of respiratory diseases, for preventing abortion
and birth, for promoting growth and influencing
the metabolism, such as clenbuterol, ethyl
4-(2-tert.-butylamino-1-hydroxyethyl)-2-cyano-
6-fluoro-phenylcarbamate hydrochloride, ~-
[[[3-(1-benzimidazolyl)-1,1-dimethvlpropyl]-
amino]-methyl-2-fluoro-4-hydroxy-benzylalcohol
methanesulphonate monohydrate, l-(4-amino-
3-cyanophenyl)-2-isopropylaminoethanol;

~-blockers for the prevention of Mastitis
Metritus Agalactie (MMA~, for reducing travel
stress, ~2-adrenergics against enteritic
diseases and for the treatment of hypoglycaemic
conditions, and for sedative purposes (e.g.

1 333770
- 14 -
clonidine, 2-[2-bromo-6-fluorophenylimino]-
imidazolidine;

benzodiazepines and derivatives thereof such
as brotizolam for sedative purposes;

antiphlogistics for anti-inflammatory treatment,
e.g. meloxicam;

somatotropin and other peptide hormones for
increasing yield;

endorphins for stimulating movement in the
rumen;

steroid hormones (natural and synthetic)
for promoting growth, e.g. oestradiol, progesterone
and the esters and synthetic derivatives
thereof such as trenbolon;

anti-parasitics for controlling endo- and
ectoparasites, such as avermectin; ; and

cardiac and circulatory substances such as
etilefrin or pimobendan.

The implants according to the invention may advantageously
be used in human medicine for administering hormones,
particularly for contraception, or as cytostatics.

It is possible to use active substances which have
both a systemic and a local effect.

A preferred field of use of the implants according
to the invention is local cancer therapy.

1 333770
- 15 -
Thus in a yet still further aspect, the present
invention provides a method of therapeutic or prophylactic
treatment of the human or non-human animal body
which method comprises implanting in said body
a physiologically active substance containing implant
according to the invention.

The Examples which follow serve to illustrate the
invention without restricting its scope in any
way.

In the Examples the following polymers are used:

Poly-D,L-lactide I [Q] = 1.0 (100 ml/g~ MW* = 123,000
Poly-D,L-lactide II [~] = 2.2 (lOOml/g) M~ = 300,000
Poly-D,L-lactide III MW = 11,500
Poly-D,L-lactic acid (M~ = 2000)

q = intrinsic viscosity

MW = molecular weight

* Determined by gas phase chromatography (standard:
polystyrene)

The Examples refer to intrinsic viscosity ( ) which
is determined from the inherent viscosity when
test concentration C tends to zero; in practical
terms under the experimental test conditions, the
intrinsic and the inherent viscosities are the
same.

Unless otherwise stated, all percentages used herein
are by weight and all molecular weights are number
average molecular weights.

1 333770
- 16 -
The Examples are discussed with reference to the
following Figures:

Figure 2 which is a graph showing the reduction
in molecular mass of the polylactide implants.

([~ = intrinsic viscosity
test conditions in vitro: isotonic phosphate buffer
pH 7.4; 37C

A: Rolled rod of poly-D,L-lactide I (solvent
method~
B: Extruded cylinder of poly-D,L-lactide I
C: poly-D,L-lactide I powder)

Fi~ure 3 which is a graph showing the reduction
in molecular mass of the polylactide implants.

(Test conditions in vitro: isotonic phosphate buffer
pH 7.4; 37C

Preparation: rolled rods of polylactide (solvent
method~
A: poly-D,L-lactide I; 7~ ethyl acetate, Tg
= 26C
D: poly-D,L-lactide II; 7% ethyl acetate, Tg
= 30C
E: poly-D,L-lactide; 7% ethyl acetate, Mp =
172C (comparison example~)

Figure 4 which is a graph showing the reduction
in molecular mass of the poly-~,L-lactide implants.

(Preparation: multi-layer film rolls, batch D
A. Administration: in vivo, sheep, s.c.
B. in vitro, test conditions: isotonic phosphate
buffer; p~ 7.4; 37C~

1 333770
- 17 -
Figure 5 which is a graph showing the reduction
in molecular mass of the poly-lactide implants.

(Preparation: rolls of film of poly-D,L-lactide
([~] = 2.9 (100 ml/g));
Batch D

A. In vitro test conditions: isotonic phosphate
buffer; pH 7.4; 37C

B. Administration: in vivo, sheep, s.c.~

Figure 6 which is a graph showing the reduction
in molecular mass of the polylactide implants.

(Test conditions in vitro: isotonic phosphate buffer;
pH 7.4; 37C

Preparation: rolls of film (solution method~
A: poly-D,L-lactide I; 7% ethyl acetate; Tg
= 26C
F: poly-D,L-lactide I: 1~ ethyl acetate; Tg
= 48C
G: poly-D,L-lactide I; 4% ethyl acetate; Tq
= 35C
H: poly-D,L-lactide II; 1% ethyl acetate; Tg
= 52C
I: poly-D,L-lactide II +
50% poly-n,L-lactic acid;
1% ethyl acetate; Tg = 30C~

Figure 7 which is a graph showing the reduction
in molecular mass of the poly-D,L-lactide implants.

(In vitro test conditions: isotonic phosphate buffer;
pH 7.4~; 37C

1 333770
- 18 -
Preparation: rolls of film (solvent method~

A: poly-D,L-lactide I; 7% ethyl acetate; Tg =
26C
F: poly-D,L-lactide I; 1~ ethyl acetate; Tg =
48C
G: poly-D,L-lactide I; 1% ethyl acetate; Tg =
35C
H: poly-D,L-lactide II; 1~ ethyl acetate; Tg=
52C
I: poly-D,L-lactide II + 50% polylactic acid
1~ ethyl acetate; Tg = 30C)

Figure 8 which is a graph showing Methotrexate
(MTX) release from polylactide implants.

(Preparation: multi-layer rods of poly-D,L-lactide
([~] = 2.2 (100 ml/g)~,

A. Administration: rat, intracerebral
B. In vitro conditions: isotonic phosphate buffer;
pH 7.4; 37C)

Figure 9 which is a graph showing release of clenbuterol
from poly-D,L-lactide implants.

In vitro test conditions: isotonic phosphate buffer;
pH 7.4; 37C

Preparation: 3-layer film rolls t[~] = 2.2 (100
ml/g~) with 23.5% by weight of clenbuterol. HCl
and 4% ethyl acetate

.

19 - 1 333770
Lactose (% by weight)

1st laYer 2nd layer 3rd layer
K O O O
L 0 25~ 0

Figure 10 which is a graph showing release of clenbuterol
from poly-D,L-lactide implants.

(_ vitro test conditions isotonic phosphate buffer;
pH 7.4; 37C.

Preparation: 3 layer film rolls containing 10~
by weight of lactose and 23.5% by weight of clenbuterol.HCl
poly-D,L-lactide II ([~] = 2.2 (100 ml/g)
Additives: L: 4% ethyl acetate
M: 1% ethyl acetate
N: 1% ethyl acetate ~ 25% poly-D,L-
lactic acid)

Figure 11 which is a graph showing reduction of
mass of poly-D,L-lactide implants.

(Preparation: double walled tubular implant of
poly-D,L-lactide III (see Example 6)
In vitro test conditions: isotonic phosphate buffer
pH 7.4, 37C.)

and Fiqure 12 which is a graph showing release
of clenbuterol from poly-D,L-lactide implants.

(Preparation: double-walled tubular implant of
poly-D,L-lactide III (see Example 6~
In vitro test conditions: isotonic phosphate buffer
pH 7.4; 37C.

Example 1

~ 33377~
- 20 -
Effects on polymer decomposition of the method
of processing, and the tacticity and molecular
mass of the carrier material polymer

25 g of poly-D,L-lactide I are dissolved in 75
g of ethyl acetate and spread out with a doctor
blade on a smooth surface to form a film. After
drying for at least 24 hours this is repeated twice
or three times until a multi-layer film 250 micrometers
thick has been produced. The film is then dried
first at 23~ and then at 40C in vacuo until a
predetermined residual solvent content is obtained,
cut into 3 x 2.5 cm pieces and shaped into rolls
(3 cm long, 2.8 mm diameter).

Implants produced by the solvent method have different
characteristics to implants obtained by extrusion,
for example, with regard to their decrease in molecular
mass in a buffer solution, i.e. they are advantageously
broken down more rapidly (see Fig. 2~. The tacticity
of the polymer plays a greater part in the rate
of breakdown than the molar mass or intrinsic viscosity
[~] (see Fig. 2). The fact that the rate of breakdown
_ vitro corresponds well to the in vivo values
is shown by Fig. 4.

A significant reduction in mass occurs after about
70 days both in vivo and in vitro, i.e. after the
limiting viscosity has fallen to a value of [~]
= 0.3 (100 ml/g~ (see Fig. 5).

The administration of the implants to sheep, rats
and mice did not produce any special reactions
over the observation period (up to 140 days), i.e.
the implants were well tolerated locally (see Table
1~ .

1 333770

Instead of using the solvent method, correspondingly
constructed shaped articles may also be produced
by extrusion (core with casing~ of granules of
polymer, active substance and additives.

~xample 2

Effects on Polymer breakdown of the residual ethYl
acetate content and the addition of polylactic
acid

Multi-layer rolls of film are produced as described
in Example 1, except that in batch I 50% of the
poly-D,L-lactide is replaced by poly-D,L-lactic
acid (molecular weight 2000).

Fig. 6 shows that the decrease in molecular weight
or mass in an aqueous medium is accelerated by
a residual ethyl acetate content of 4 or 7~ but
not by a content of 1%. The addition of 50% of
poly-D,L-lactic acid results in a very marked acceleration
of polymer decomposition.

The reduction in mass correlates with the reduction
in molecular mass a described in Example 1 (see
Fig. 7)-

~xample 3

Effects of substrate structure on release of active
-
substance

25 g of poly-D,L-lactide II ([~] = 2.2 (100 ml/g)~
are dissolved in 75 g of ehtyl acetate, 5.0 g of
methotrexate (MTX) (particle size 30 micrometers
- x - 60 micrometers) are suspended therein and
three-layer films are produced analogously to Example

- 22 - I 3 3 37 7 0
1 with a layer thickness of 0.80 mm, the upper
and lower polymer layers remaining free from active
substance. After a residual solvent content of
7% has been obtained, the multi-layer film is cut
into strips of 1 x 1 x 10 mm (unlike Example 1).

MTX is released from implants of this kind at a
constant rate of 63 micrograms per day in the period
from 10 to about 60 days, both in vivo and in vitro,
without any significant reduction in the polymer
molecular mass (see Fig. 8).

Example 4

Effects of lactose addition on the release of active
substance

8.8g of poly-D,L-lactide II ([~] = 2.2 (100 ml/g))are
dissolved in 45 g of ethyl acetate and 2.7 g of
clenbuterol.HCl (20 micrometers = x = 53 micrometers)
are suspended therein and a three-layer film is
prepared as in Example 1. In batch L, an additional
25~ by weight of lactose (particle size: 1 - 5
micrometers~ is suspended in the polymer solution
which is used to form the central layer.

Fig. 9 shows that the addition of lactose accelerates
the release of clenbuterol in an aqueous medium
and thus provides a method of controlling the release.

Example 5

Effects of polylact;c acid addition on the release
of active substance

The three-layered film roll L of Example 4 is compared
with a preparation produced analogously in which

1 33377~
- 23 -
25% of the poly-D,L-lactide II is replaced by poly-
D,L-lactic acid (molecular mass 2000~.

Whereas the release of clenbuterol in an aqueous
medium is greatly accelerated by the addition of
polylactic acid, the residual ethyl acetate content
in the range from 1 - 4~ had no effect on the release
characteristics.

Polylactic acid can therefore be used like lactose
as an additive which will control the release of
the active substance.

Example 6

Effects of the substrate structure on the release
of active substance (Implant type E)

Poly-D,L-lactide III containing no active substance
and a fusion granulate consisting of 3 parts by
weight of poly-n~L-lactide III and 1 part by weight
of clenbuterol hydrochloride (20 - 53 micrometers)
are processed at 90C (mass temperature) to form
a double-walled tube (this can be done either by
using a suitable extruder or by injection moulding~.
An implant of type E - produced according to Example
6 - having the following dimensions was used for
_ vitro tests on the breakdown of polymer and
release of active substance: length 10 mm, diameter
of central cavity 2 mm, overall diameter 5mm; outer
casing (free from and impervious to active substance~,
wall thickness 0.5 mm; inner tube containing active
substance, wall thickness 1.0 mm.

Fig. 11 shows the substantially linear breakdown
of the polymer mass in vitro with a half life of
about 70 days whilst Fig. 12 shows the substantially
linear release of clenbuterol.

~ 333770
- 24 -
Table I ~athology and histology of the implants

Findings


up to about 60 days: from about 100 daYs:
slight capsule form- slight scarring, no
ation, slight in- inflammation and no
flammation, usual other findings
macrophage forma-
tion


Species Adminis- individual cell
tration detritus

Sheep s.c., reaction normal yes
behind
the ear


Mouse s.c. reaction normal yes
neck
s.c. reaction normal yes
back


Rat intra- reaction normal yes
cere- -
bral
intra- reaction normal yes
tumoral,
hack

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date 1995-01-03
(22) Filed 1988-10-07
(45) Issued 1995-01-03
Expired 2012-01-03

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1988-10-07
Registration of a document - section 124 $0.00 1989-01-03
Maintenance Fee - Patent - Old Act 2 1997-01-03 $100.00 1996-12-19
Maintenance Fee - Patent - Old Act 3 1998-01-05 $100.00 1997-12-22
Maintenance Fee - Patent - Old Act 4 1999-01-04 $100.00 1998-12-23
Maintenance Fee - Patent - Old Act 5 2000-01-04 $150.00 1999-12-13
Maintenance Fee - Patent - Old Act 6 2001-01-03 $150.00 2000-12-14
Maintenance Fee - Patent - Old Act 7 2002-01-03 $150.00 2001-12-20
Maintenance Fee - Patent - Old Act 8 2003-01-03 $150.00 2002-12-17
Maintenance Fee - Patent - Old Act 9 2004-01-05 $150.00 2003-12-23
Maintenance Fee - Patent - Old Act 10 2005-01-04 $250.00 2004-12-22
Maintenance Fee - Patent - Old Act 11 2006-01-03 $250.00 2005-12-23
Maintenance Fee - Patent - Old Act 12 2007-01-03 $250.00 2006-12-19
Maintenance Fee - Patent - Old Act 13 2008-01-03 $250.00 2007-12-24
Maintenance Fee - Patent - Old Act 14 2009-01-05 $250.00 2008-12-22
Maintenance Fee - Patent - Old Act 15 2010-01-04 $450.00 2009-12-17
Maintenance Fee - Patent - Old Act 16 2011-01-04 $450.00 2010-12-23
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Past Owners on Record
ENTENMANN, GUNTHER
KERN, OTTO
MIKHAIL, MICHEL
STRICKER, HERBERT
ZIERENBERG, BERND
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Prosecution Correspondence 1992-07-10 4 121
Prosecution Correspondence 1994-02-14 1 27
PCT Correspondence 1994-10-12 1 35
Examiner Requisition 1993-10-13 2 71
Examiner Requisition 1992-03-13 1 60
Claims 1995-01-03 4 128
Drawings 1995-01-03 6 47
Cover Page 1995-01-03 1 25
Abstract 1995-01-03 1 13
Description 1995-01-03 24 797
Representative Drawing 2000-08-04 1 2
Fees 1996-12-19 1 88